Hypoxia-induced ZEB1 promotes cervical cancer progression via CCL8-dependent tumour-associated macrophage recruitment

• Published in: Cell death & disease 2019-07, Vol.10 (7), p.508-11, Article 508
• Main Authors: Chen, Xiao-Jing, Deng, Yuan-Run, Wang, Zi-Ci, Wei, Wen-Fei, Zhou, Chen-Fei, Zhang, Yan-Mei, Yan, Rui-Ming, Liang, Luo-Jiao, Zhong, Mei, Liang, Li, Wu, Sha, Wang, Wei
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/21; 13/44; 13/51; 13/89; 14/19; 38/90; 631/67/1517/1371; 631/67/327; 631/80/86/2371; 82/80; Adult; Antibodies; Biochemistry; Biomedical and Life Sciences; Blotting, Western; CCR2 protein; CD163 antigen; Cell Biology; Cell Culture; Cell Line, Tumor; Cervical cancer; Cervix; Chemokine CCL8 - genetics; Chemokine CCL8 - metabolism; Chemokines; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Genomes; Human papillomavirus; Humans; Hypoxia; Hypoxia - metabolism; Immunohistochemistry; Immunology; Leukocyte migration; Life Sciences; Macrophages; Macrophages - metabolism; Metastases; Microenvironments; Middle Aged; Monocyte chemoattractant protein 1; NF-kappa B - metabolism; NF-κB protein; Reverse Transcriptase Polymerase Chain Reaction; Transcription; Tumor microenvironment; Tumor Microenvironment - genetics; Tumor Microenvironment - physiology; Tumors; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Zinc Finger E-box-Binding Homeobox 1 - genetics; Zinc Finger E-box-Binding Homeobox 1 - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1748-1

The accumulation of tumour-associated macrophages (TAMs) in the hypoxic tumour microenvironment (TME) is associated with malignant progression in cancer. However, the mechanisms by which the hypoxic TME facilitates TAM infiltration are not fully understood. This study showed that high ZEB1 expression in hypoxic cervical cancer cell islets was positively correlated with CD163 + TAM accumulation. ZEB1 in hypoxic cancer cells promoted the migration of TAMs in vitro and altered the expression of multiple chemokines, especially CCL8. Mechanistically, hypoxia-induced ZEB1 activated the transcription of CCL8, which attracted macrophages via the CCR2–NF-κB pathway. Furthermore, ZEB1 and CCL8 were independent prognostic factors in cervical cancer patients based on The Cancer Genome Atlas (TCGA) data analysis. In conclusion, hypoxia-induced ZEB1 exerts unexpected functions in cancer progression by fostering a prometastatic environment through increased CCL8 secretion and TAM recruitment; thus, ZEB1 may serve as a candidate biomarker of tumour progression and provide a potential target for disrupting hypoxia-mediated TME remodelling.